Over 1 billion people worldwide, and 31 percent of Americans, have hypertension or high blood pressure. Approximately 74.5 million adults over 20 years of age in the United States have high blood pressure. High blood pressure is characterized by a systolic blood pressure (SBP) of greater than 140 millimeters of mercury (mm Hg), a diastolic blood pressure (DBP) of greater than 90 mm Hg, or requiring antihypertensive medication. High blood pressure is the leading contributor to global mortality, with prevalence of 26.2 percent in the year 2000. Uncontrolled high blood pressure increases risk for stroke, diabetes, coronary heart disease, congestive heart failure, and chronic kidney disease. High blood pressure is associated with 4.9 to 5.1 years shorter life expectancy in women and men, respectively. Approximately three fourths of adults with cardiovascular disease (CVD) comorbidities experience poor control rates for systolic hypertension.
Long term trends indicate that approximately 55 percent of cases of high blood pressure have a heritable cause. In addition to heritability, risk factors for high blood pressure include increasing age, ethnicity, and behavior. Populations with darker skin color may have an unmet medical need for treatment of high blood pressure. Prevalence in African Americans in the United States is now 41.4 percent in men and 44.0 percent in women. The unmet medical need for new effective antihypertensive agents is paralleled by the $76.6 billion annual cost associated with high blood pressure.
Current therapy strategies for hypertension involve drugs to reduce cardiac output, decrease myocardial contractility, or lower peripheral resistance. Classes of current antihypertensive treatments include diuretics, adrenergic receptor antagonists, benzodiazepines, calcium channel blockers, renin inhibitors (aliskiren), angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, aldosterone receptor antagonists, vasodilators, adrenergic receptor agonists, endothelin receptor blockers (bosentan), and other emerging therapeutic approaches.
Diuretic therapies include loop diuretics (bumetanide, ethacrynic acid, furosemide, and torsemide), thiazide diuretics (epitizide, hydrochlorthiazide, chlorthiazide, and bendroflumethiazide), thiazide-like diuretics (indpamide, chlorthialidone, and metolazone), and potassium sparing (amiloride, triamterene, and spironolactone). Adrenergic receptor antagonists include beta-blockers (atenolol, metoprolol, nadolol, nebivolol, oxprenolol, propranolol, and timolol), alpha blockers (doxazosin, phentolamine, indoramin, phenoxybenzamine, prazocin, terazosin, and tolazoline), mixed alpha/beta blockers (bucindolol, carbedilol, and labetalol), and indirect or central (guanethidine, reserpine, and mecamylamine, which is an anti-nicotinic). Calcium channel blockers include dihydropyridines (amlodipine, cilnidipine, felodipine, isradipine, lercanidipine, levamlodipine, nicardipine, nimodipine, and nitrendipine). ACE inhibitors include drugs such as captopril, enalapril, fosinopril, lisinopril, perindopril, quinapril, ramipril, trandolapril, and benazepril. Angiotensin II receptor antagonists include drugs such as candesartan, eprosartan, irdesartan, losartan, olmesartan, telmisartan, and valsartan. Aldosterone receptor antagonists include drugs such as eplerenone and spironolactone, which treats heart failure. Vasodilators include drugs such as minoxedil, sodium nitroprusside, and hydrazaline. Adrenergic receptor agonists of the subclass α2, include clonidine, guanabenz, guanfacine, methyldopa, and moxonidine. Other emerging therapeutic approaches include blood pressure vaccine CYT006-AngQb and renal denervation using a radiofrequency ablation catheter.
Current approaches using substrate inhibitors are unable to separate inhibition of cytochrome P450, family 3, subfamily A, polypeptide 5 (CYP3A5) and cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4). Substrate inhibitors for the CYP3A family of enzymes typically have a molecular weight of approximately 150 to 350 grams per mole, and sit in the active site of a receptor to block the enzymes from binding to the receptor. Substrate inhibitors are broad, in that the substrate inhibitors for CYP3A5 also block or inhibit CYP3A4 along with other CYP3A enzymes and potentially other cytochrome P450s in the body. The lack of specificity of substrate inhibitors can result in undesirable side effects, such as inhibiting or decreasing the metabolic activity of other cytochrome P450s. Substrate inhibitors can further cause reactive metabolite formation, for example, when molecular oxygen (O2) is broken from O2 into reactive oxygen during CYP3A5 metabolism. Reactive metabolite byproducts of CYP3A5 metabolism create intermediate superoxides that can become hydroxyl radicals, which can accumulate in the kidney and are damaging to cells.
Some patients are refractory to the current standard of care in managing hypertension and continue to suffer from uncontrolled hypertension while using current treatments. Emerging populations of individuals are not able to control blood pressure with the wide variety of current medications currently available to treat hypertension. Additionally, renal transplant patients taking antirejection immune suppression drugs such as cyclosporin A or tacrolimus are at risk of kidney transplant rejection due to enhanced renal clearance from CYP3A5 metabolism.
Attempts to unravel the strong genetic linkage to hypertension have not led to genetic profiles for prediction or development of new therapeutics to treat hypertension. Initial genome wide associative studies (GWAS) to identify genes contributing to human hypertension failed to identify any single-nucleotide polymorphisms (SNPs) corresponding to hypertension. Subsequently, larger GWAS identified genes associated with hypertension in African Americans and variants contributing to population SBP, but the studies fail to reproducibly identify the same genes, or genes with impact greater than 1 to 2 mm Hg in blood pressure, or provide mechanistic insights into the genetic basis of hypertension. The GWAS do not lead to useful genetic profiles for predicting hypertension. The apparent contradiction between heritability of hypertension and failure of GWAS to find significant genetic linkage can be explained by the emerging complexity in ribonucleic acid (RNA) expression.